CA3019312A1 - Compositions for reducing blood lipid levels and methods for manufacturing thereof - Google Patents
Compositions for reducing blood lipid levels and methods for manufacturing thereof Download PDFInfo
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Abstract
A composition for reducing blood lipid level is disclosed. The composition comprises a Monascus component and a phytosterol component. In some embodiments, the phytosterol component comprises a phytosterol or a phytosterol ester. In some embodiments, the phytosterol component comprises phytosterol fine particles to increase the bioavailability of the phytosterol in the intestine.
Description
COMPOSITIONS FOR REDUCING BLOOD LIPID LEVELS AND METHODS
FOR MANUFACTURING THEREOF
Technical Field [0001] The present invention relates in general to compositions or pharmaceutical formulations for reducing blood lipid levels and methods for manufacturing thereof.
Background
FOR MANUFACTURING THEREOF
Technical Field [0001] The present invention relates in general to compositions or pharmaceutical formulations for reducing blood lipid levels and methods for manufacturing thereof.
Background
[0002] Cardiovascular diseases, including coronary heart disease, myocardial infarction, high blood pressure, are a common disease in many countries. A
large number of long-term clinical and laboratory studies have shown that high levels of serum cholesterol, especially high levels of low density lipoprotein cholesterol is an independent risk factor for the development of coronary heart disease, myocardial infarction and other cardiovascular diseases. Lowering serum cholesterol levels is recognized as an important measure to reduce or delay the incidence of cardiovascular and cerebrovascular diseases.
Detailed Description
large number of long-term clinical and laboratory studies have shown that high levels of serum cholesterol, especially high levels of low density lipoprotein cholesterol is an independent risk factor for the development of coronary heart disease, myocardial infarction and other cardiovascular diseases. Lowering serum cholesterol levels is recognized as an important measure to reduce or delay the incidence of cardiovascular and cerebrovascular diseases.
Detailed Description
[0003] Throughout the following description, specific details are set forth in order to provide a more thorough understanding of the invention. However, the invention may be practiced without these particulars. In other instances, well known elements have not been shown or described in detail to avoid unnecessarily obscuring the invention. Accordingly, the specification and drawings are to be regarded in an illustrative, rather than a restrictive, sense.
[0004] There are several major sources of cholesterol in the human body. As a first source, cholesterol can be made by biosynthesis derived from acetyl coenzyme A
as precursor raw materials. A second source is the intestinal absorption of cholesterol from food and bile from the liver and other organs. In the intestine about 50%
of the cholesterol from food and bile is absorbed. Therefore, two ways to control blood cholesterol level are to control cholesterol biosynthesis in vivo and to control intestinal absorption of cholesterol.
[00051 In the cholesterol synthesis pathway in the liver and other organs, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is the rate-limiting enzyme in the cholesterol synthesis. Current common lipid-lowering drugs (such as statins) on the market work by inhibiting HMG-CoA reductase, to reduce cholesterol synthesis in the liver to reduce serum cholesterol levels. Statins, including lovastatin, although effective in reducing serum cholesterol levels, can also have some toxic side effects on the kidneys and liver, and may cause rhabdomyolysis. Rhabdomyolysis is a condition in which damaged skeletal muscle breaks down. Due to its side effects at least one synthetic statin was withdrawn from market.
[00061 Red yeast rice (known as "Hong Qu Mi" in Chinese language) is a bright reddish purple fermented rice, which acquires its colour from being cultivated with the mold Monascus purpureus. Monascus is a genus of mold or fungus, also known as red yeast. Monascus purpureus is a species of mold that is purplish-red in color.
During growth, Monascus spp. break down starch substrate into several metabolites, including pigments produced as secondary metabolites. The structure of pigments depends on type of substrate and other specific factors during culture, such as pH, temperature, and moisture content.
[0007] This fungus is most important because of its use, in the form of red yeast rice, in the production of certain fermented foods in China. However, discovery of cholesterol-lowering statins produced by the mold has prompted research into its possible medical uses. It produces a number of statins. The naturally occurring lovastatins and analogs are called monacolins K, L, J, and also occur in their hydroxyl acid forms along with dehydroxymonacolin and compactin. The prescription drug lovastatin, identical to monacolin K, is the principal statin produced by M.
purpureus. The related fungi M. ruber and M. pilosus are also used in some applications.
[0008] The chemical structure of monacolin K is shown below:
HO4c.r.0 H
[00091 Red yeast rice is produced by cultivating the red yeast or fungus strain Monascus purpureus on rice. The rice is first soaked in water until the grains are fully saturated. The raw soaked rice can then either be directly inoculated or it can be steamed for the purpose of sterilizing and cooking the grains prior to inoculation.
Inoculation is done by mixing either M. purpureus spores or powdered red yeast rice together with the rice that is being treated. The mix is then incubated in an environment around room temperature for 3-6 days. During this period of time, the rice should be fully cultured with M. purpureus, with each rice grain turning bright red in its core and reddish purple on the outside. The fully cultured rice can be cooked and pasteurized as a wet paste, or dried and pulverized as a fine powder.
[0010] In recent years, it is discovered that red yeast rice has the effect of lowering serum cholesterol and triglyceride. Analysis of the components of red yeast rice preparations showed that one of the important active ingredients is monacolin K which is identical to lovastatin. Lovastatin inhibits hepatic HMG-CoA reductase to reduce cholesterol synthesis in the liver, thus reducing serum cholesterol levels.
Lovastatin also reduce serum triglycerides levels. Red yeast extract can inhibit the enzyme activity of HMG-CoA reductase in human liver cells. Thus Monascus has lipid-lowering effect of lovastatin which is attributed at least in part to inhibiting the synthesis of cholesterol in the liver. Because red yeast rice contains lovastatin and lovastatin may have potential side effects for the kidney, liver and muscle, these side effects cannot be completely ruled out. Further, Monascus extracts may also contain a mycotoxin called citrinin. Citrinin is a polyketide mycotoxin, which is a secondary metabolite of some fungi species. Citrinin decomposes at temperatures higher than 175 C, providing that it is under dry conditions. When water is present, the decomposition temperature is around 100 C.
[0011] Phytosterols, which encompass plant sterols and stanols, are phytosteroids, similar to cholesterol, which occur in plants and vary only in carbon side chains and/or presence or absence of a double bond. Stanols are saturated sterols, having no double bonds in the sterol ring structure. More than 200 sterols and related compounds have been identified. Free phytosterols extracted from oils are insoluble in water, relatively insoluble in oil, and soluble in alcohols. Phytosterols are found in the cell membranes of plants, where they play important roles. Therefore, they are also known as plant sterols. Some common phytosterols are campesterol, sitosterol and stigmasterol.
Phytoterols can be present in the free form and/or as fatty acid esters and glycolipids.
[0012] The structure of campesterol is shown below:
H
HO
[0013] The structure of sitosterol is shown below:
) H Fi HCLJ
=
as precursor raw materials. A second source is the intestinal absorption of cholesterol from food and bile from the liver and other organs. In the intestine about 50%
of the cholesterol from food and bile is absorbed. Therefore, two ways to control blood cholesterol level are to control cholesterol biosynthesis in vivo and to control intestinal absorption of cholesterol.
[00051 In the cholesterol synthesis pathway in the liver and other organs, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is the rate-limiting enzyme in the cholesterol synthesis. Current common lipid-lowering drugs (such as statins) on the market work by inhibiting HMG-CoA reductase, to reduce cholesterol synthesis in the liver to reduce serum cholesterol levels. Statins, including lovastatin, although effective in reducing serum cholesterol levels, can also have some toxic side effects on the kidneys and liver, and may cause rhabdomyolysis. Rhabdomyolysis is a condition in which damaged skeletal muscle breaks down. Due to its side effects at least one synthetic statin was withdrawn from market.
[00061 Red yeast rice (known as "Hong Qu Mi" in Chinese language) is a bright reddish purple fermented rice, which acquires its colour from being cultivated with the mold Monascus purpureus. Monascus is a genus of mold or fungus, also known as red yeast. Monascus purpureus is a species of mold that is purplish-red in color.
During growth, Monascus spp. break down starch substrate into several metabolites, including pigments produced as secondary metabolites. The structure of pigments depends on type of substrate and other specific factors during culture, such as pH, temperature, and moisture content.
[0007] This fungus is most important because of its use, in the form of red yeast rice, in the production of certain fermented foods in China. However, discovery of cholesterol-lowering statins produced by the mold has prompted research into its possible medical uses. It produces a number of statins. The naturally occurring lovastatins and analogs are called monacolins K, L, J, and also occur in their hydroxyl acid forms along with dehydroxymonacolin and compactin. The prescription drug lovastatin, identical to monacolin K, is the principal statin produced by M.
purpureus. The related fungi M. ruber and M. pilosus are also used in some applications.
[0008] The chemical structure of monacolin K is shown below:
HO4c.r.0 H
[00091 Red yeast rice is produced by cultivating the red yeast or fungus strain Monascus purpureus on rice. The rice is first soaked in water until the grains are fully saturated. The raw soaked rice can then either be directly inoculated or it can be steamed for the purpose of sterilizing and cooking the grains prior to inoculation.
Inoculation is done by mixing either M. purpureus spores or powdered red yeast rice together with the rice that is being treated. The mix is then incubated in an environment around room temperature for 3-6 days. During this period of time, the rice should be fully cultured with M. purpureus, with each rice grain turning bright red in its core and reddish purple on the outside. The fully cultured rice can be cooked and pasteurized as a wet paste, or dried and pulverized as a fine powder.
[0010] In recent years, it is discovered that red yeast rice has the effect of lowering serum cholesterol and triglyceride. Analysis of the components of red yeast rice preparations showed that one of the important active ingredients is monacolin K which is identical to lovastatin. Lovastatin inhibits hepatic HMG-CoA reductase to reduce cholesterol synthesis in the liver, thus reducing serum cholesterol levels.
Lovastatin also reduce serum triglycerides levels. Red yeast extract can inhibit the enzyme activity of HMG-CoA reductase in human liver cells. Thus Monascus has lipid-lowering effect of lovastatin which is attributed at least in part to inhibiting the synthesis of cholesterol in the liver. Because red yeast rice contains lovastatin and lovastatin may have potential side effects for the kidney, liver and muscle, these side effects cannot be completely ruled out. Further, Monascus extracts may also contain a mycotoxin called citrinin. Citrinin is a polyketide mycotoxin, which is a secondary metabolite of some fungi species. Citrinin decomposes at temperatures higher than 175 C, providing that it is under dry conditions. When water is present, the decomposition temperature is around 100 C.
[0011] Phytosterols, which encompass plant sterols and stanols, are phytosteroids, similar to cholesterol, which occur in plants and vary only in carbon side chains and/or presence or absence of a double bond. Stanols are saturated sterols, having no double bonds in the sterol ring structure. More than 200 sterols and related compounds have been identified. Free phytosterols extracted from oils are insoluble in water, relatively insoluble in oil, and soluble in alcohols. Phytosterols are found in the cell membranes of plants, where they play important roles. Therefore, they are also known as plant sterols. Some common phytosterols are campesterol, sitosterol and stigmasterol.
Phytoterols can be present in the free form and/or as fatty acid esters and glycolipids.
[0012] The structure of campesterol is shown below:
H
HO
[0013] The structure of sitosterol is shown below:
) H Fi HCLJ
=
- 5 -[0014] The structure of stigmasterol is shown below:
re+cj -,õ-õ,,, 1 ' T ) ,11 , F10)::
[0015] A problem with using Monascus or Monascus preparation is that it contains lovastatin which may have side effects on human kidney, liver, and muscle.
Additionally, Monascus or Monascus preparation only reduces cholesterol synthesis in the liver, but does not inhibit the absorption of cholesterol from food in the intestine.
Such single function is not optimal. If the dosage of Monascus or Monascus preparation is increased to a higher level, the side effects caused by lovastatin will also be increased. This is undesirable. It would be desirable to provide a solution through which one can effectively reduce cholesterol synthesis in the liver, and can effectively inhibit cholesterol absorption in the intestine, to reduce serum cholesterol levels from different sources without increasing the side effects, through the combination of two different blood lipid lowering mechanisms.
[0016] One aspect of the invention relates to compositions for reducing blood lipid levels (e.g. blood cholesterol levels). In some embodiments, the composition comprises a Monascus component and a phytosterol component. In some embodiments, the composition comprises a Monascus preparation and a phytosterol ester component. In some embodiments, the composition comprises a Monascus preparation and a chemical derivative of phytosterol. In some embodiments, the phytosterol component comprises a blend of phytosterol and phytostanol. Phytostanols are a fully-saturated subgroup of phytosterols (containing no double bonds). In some embodiments, the phytosterol component comprises a blend of phytosterol and phytostanols, and the percentage of phytosterol in the blend is less than 10%, and the percentage of phytostanols in the blend is greater than 90%. In some embodiments, the phytosterol component comprises only fully-saturated phytostanols. In some cases, phytostanols
re+cj -,õ-õ,,, 1 ' T ) ,11 , F10)::
[0015] A problem with using Monascus or Monascus preparation is that it contains lovastatin which may have side effects on human kidney, liver, and muscle.
Additionally, Monascus or Monascus preparation only reduces cholesterol synthesis in the liver, but does not inhibit the absorption of cholesterol from food in the intestine.
Such single function is not optimal. If the dosage of Monascus or Monascus preparation is increased to a higher level, the side effects caused by lovastatin will also be increased. This is undesirable. It would be desirable to provide a solution through which one can effectively reduce cholesterol synthesis in the liver, and can effectively inhibit cholesterol absorption in the intestine, to reduce serum cholesterol levels from different sources without increasing the side effects, through the combination of two different blood lipid lowering mechanisms.
[0016] One aspect of the invention relates to compositions for reducing blood lipid levels (e.g. blood cholesterol levels). In some embodiments, the composition comprises a Monascus component and a phytosterol component. In some embodiments, the composition comprises a Monascus preparation and a phytosterol ester component. In some embodiments, the composition comprises a Monascus preparation and a chemical derivative of phytosterol. In some embodiments, the phytosterol component comprises a blend of phytosterol and phytostanol. Phytostanols are a fully-saturated subgroup of phytosterols (containing no double bonds). In some embodiments, the phytosterol component comprises a blend of phytosterol and phytostanols, and the percentage of phytosterol in the blend is less than 10%, and the percentage of phytostanols in the blend is greater than 90%. In some embodiments, the phytosterol component comprises only fully-saturated phytostanols. In some cases, phytostanols
- 6 -are more advantageous because they have a lower estimated intestinal absorption rate than phytosterols. This may be advantageous for patients suffering from sitosterolemia.
In some embodiments, the phytosterol component comprises only fully-saturated phytostanols derived from plant species. In some embodiments, the phytosterol component comprises only synthetic phytostanols. This may be advantageous for patients suffering from sitosterolemia. In some embodiments, the phytosterol component comprises only phytosterol compounds that have at least two carbon-carbon double bonds. In some embodiments, the phytosterol component comprises only phytosterol compounds that have at least three carbon-carbon double bonds. In some embodiments, the phytosterol component comprises only phytosterol compounds that have at least four carbon-carbon double bonds. The carbon-carbon double bonds can increase the intestinal absorption rate and may be beneficial for patients with intestinal related medical conditions. Some individuals may have intestinal sensitivity to phytostanols, but not to phytosterols. On the other hand, some individuals may have intestinal sensitivity to phytosterols, but not to phytostanols.
Grain species are rich in saturated phytostanols, and legume species are rich in unsaturated phytosterols.
[0017] The Monascus preparation of this aspect of the invention can be a Monascus extract in a form such as dried powders or solutions.
[0018] The phytosterol component of this aspect of the invention can be phytosterol fine particles of 80 mesh or more or phytosterol particles in nanometer range.
[0019] The phytosterol component may be free phytosterols or the ester of a phytosterol bound to a fatty acid.
[0020] The phytosterol component may be a phytosterol derivative created through chemical reactions or a mixture of phytosterol with other chemical or biological
In some embodiments, the phytosterol component comprises only fully-saturated phytostanols derived from plant species. In some embodiments, the phytosterol component comprises only synthetic phytostanols. This may be advantageous for patients suffering from sitosterolemia. In some embodiments, the phytosterol component comprises only phytosterol compounds that have at least two carbon-carbon double bonds. In some embodiments, the phytosterol component comprises only phytosterol compounds that have at least three carbon-carbon double bonds. In some embodiments, the phytosterol component comprises only phytosterol compounds that have at least four carbon-carbon double bonds. The carbon-carbon double bonds can increase the intestinal absorption rate and may be beneficial for patients with intestinal related medical conditions. Some individuals may have intestinal sensitivity to phytostanols, but not to phytosterols. On the other hand, some individuals may have intestinal sensitivity to phytosterols, but not to phytostanols.
Grain species are rich in saturated phytostanols, and legume species are rich in unsaturated phytosterols.
[0017] The Monascus preparation of this aspect of the invention can be a Monascus extract in a form such as dried powders or solutions.
[0018] The phytosterol component of this aspect of the invention can be phytosterol fine particles of 80 mesh or more or phytosterol particles in nanometer range.
[0019] The phytosterol component may be free phytosterols or the ester of a phytosterol bound to a fatty acid.
[0020] The phytosterol component may be a phytosterol derivative created through chemical reactions or a mixture of phytosterol with other chemical or biological
- 7 -substances.
[0021] The composition may be provided in a capsule, or a tablet, or a chewing gum, or a block, or some other oral pharmaceutical dosage forms. The composition can also be incorporated into a beverage, a food item, or a pharmaceutical composition.
[00221 One aspect of the invention relates to methods for preparing said compositions. In some embodiments, the Monascus component and the phytosterol component are dissolved together in an organic solvent or a mixed organic solvent (e.g., 70-100% methanol, ethanol or chloroform). The mixture of the Monascus preparation and the phytosterol is obtained by evaporation drying of the solution. The organic solvent can be an edible oil (e.g., vegetable oil, soybean oil, peanut oil, corn oil, sesame oil, cottonseed oil, etc.), or nutritional oil (evening primrose oil, pine oil, linseed oil, borage seed oil, fish oil, cod liver oil), spice oil (such as ginger oil, naringin oil, eucalyptus oil, wintergreen oil, patchouli oil, lavender oil, etc.), or edible emulsifier (such as stearoyl lactylates, phosphatidylethanolamine, glyceryl monostearate, sucrose fatty acid esters, or the like). The weight ratio of the solvent oil or edible emulsifier to phytosterol is from 0 to 2:1, e.g., 1:1 to 2:1.
[0023] In some embodiments, the phytosterols can form an ester with the free or bound fatty acids in the edible oil (e.g., vegetable oil, soybean oil, peanut oil, corn oil, sesame oil, cottonseed oil, etc.), or nutritional oil (evening primrose oil, pine oil, linseed oil, borage seed oil, fish oil, cod liver oil), spice oil (such as ginger oil, naringin oil, eucalyptus oil, wintergreen oil, patchouli oil, lavender oil, etc.), or edible emulsifier (such as stearoyl lactylates, phosphatidylethanolamine, glyceryl monostearate, sucrose fatty acid esters, or the like).
[0024] In some embodiments, the Monascus preparation or the phytosterol is dissolved with an edible oil (e.g., vegetable oil, soybean oil, peanut oil, corn oil, sesame oil, cottonseed oil, etc.), or nutritional oil (evening primrose oil, pine oil, linseed oil,
[0021] The composition may be provided in a capsule, or a tablet, or a chewing gum, or a block, or some other oral pharmaceutical dosage forms. The composition can also be incorporated into a beverage, a food item, or a pharmaceutical composition.
[00221 One aspect of the invention relates to methods for preparing said compositions. In some embodiments, the Monascus component and the phytosterol component are dissolved together in an organic solvent or a mixed organic solvent (e.g., 70-100% methanol, ethanol or chloroform). The mixture of the Monascus preparation and the phytosterol is obtained by evaporation drying of the solution. The organic solvent can be an edible oil (e.g., vegetable oil, soybean oil, peanut oil, corn oil, sesame oil, cottonseed oil, etc.), or nutritional oil (evening primrose oil, pine oil, linseed oil, borage seed oil, fish oil, cod liver oil), spice oil (such as ginger oil, naringin oil, eucalyptus oil, wintergreen oil, patchouli oil, lavender oil, etc.), or edible emulsifier (such as stearoyl lactylates, phosphatidylethanolamine, glyceryl monostearate, sucrose fatty acid esters, or the like). The weight ratio of the solvent oil or edible emulsifier to phytosterol is from 0 to 2:1, e.g., 1:1 to 2:1.
[0023] In some embodiments, the phytosterols can form an ester with the free or bound fatty acids in the edible oil (e.g., vegetable oil, soybean oil, peanut oil, corn oil, sesame oil, cottonseed oil, etc.), or nutritional oil (evening primrose oil, pine oil, linseed oil, borage seed oil, fish oil, cod liver oil), spice oil (such as ginger oil, naringin oil, eucalyptus oil, wintergreen oil, patchouli oil, lavender oil, etc.), or edible emulsifier (such as stearoyl lactylates, phosphatidylethanolamine, glyceryl monostearate, sucrose fatty acid esters, or the like).
[0024] In some embodiments, the Monascus preparation or the phytosterol is dissolved with an edible oil (e.g., vegetable oil, soybean oil, peanut oil, corn oil, sesame oil, cottonseed oil, etc.), or nutritional oil (evening primrose oil, pine oil, linseed oil,
- 8 -borage seed oil, fish oil, cod liver oil), spice oil (such as ginger oil, naringin oil, eucalyptus oil, wintergreen oil, patchouli oil, lavender oil, etc.), or edible emulsifier (such as stearoyl lactylates, phosphatidylethanolamine, glyceryl monostearate, sucrose fatty acid esters, or the like) in an organic solvent or a mixed organic solvent (e.g., 70-100% methanol, ethanol or chloroform). The solution is then dried by evaporation drying of the solution and then mixed. The weight ratio of the solvent oil or edible emulsifier to phytosterol is from 0 to 2:1, e.g., 1:1 to 2:1.
[0025] In some embodiments, the Monascus component or phytosterols may be mixed with an edible oil (e.g., vegetable oil, soybean oil, peanut oil, corn oil, sesame oil, cottonseed oil, etc.), or nutritional oil (evening primrose oil, pine oil, linseed oil, borage seed oil, fish oil, cod liver oil), spice oil (such as ginger oil, naringin oil, eucalyptus oil, wintergreen oil, patchouli oil, lavender oil, etc.), or edible emulsifier (such as stearoyl lactylates, phosphatidylethanolamine, glyceryl monostearate, sucrose fatty acid esters, or the like) in a heated eutectic mixture. The weight ratio of the oil or edible emulsifier to phytosterol is from 0 to 2:1, e.g., 1:1 to 2:1.
[0026] In some embodiments, in the compositions, the weight ratio of monacolins, or monacolins K and L, or monacolin K to phytosterol is 1:4000 to 1:5.
[0027] For dosage of said compositions comprising a Monascus preparation and a phytosterol component, the amount of phytosterol should be 0.4 to 10 grams per day. For dosage of said compositions comprising a Monascus preparation and a phytosterol component, the amount of monacolins, or monacolins K and L, or monacolin K should be 1-80 mg per day.
[0028] Monascus refers to Monascus fungus (e.g., Monascus, Monascus purpureus, Monascus ruber, Monascus anka, Monascus pilosus, Monascus floridanus, Monascus pallens, Monascus sanguineus etc.) which is prepared by rice-based bio-reaction (e.g., fermentation) and which contains monacolins compounds. The Monascus preparation
[0025] In some embodiments, the Monascus component or phytosterols may be mixed with an edible oil (e.g., vegetable oil, soybean oil, peanut oil, corn oil, sesame oil, cottonseed oil, etc.), or nutritional oil (evening primrose oil, pine oil, linseed oil, borage seed oil, fish oil, cod liver oil), spice oil (such as ginger oil, naringin oil, eucalyptus oil, wintergreen oil, patchouli oil, lavender oil, etc.), or edible emulsifier (such as stearoyl lactylates, phosphatidylethanolamine, glyceryl monostearate, sucrose fatty acid esters, or the like) in a heated eutectic mixture. The weight ratio of the oil or edible emulsifier to phytosterol is from 0 to 2:1, e.g., 1:1 to 2:1.
[0026] In some embodiments, in the compositions, the weight ratio of monacolins, or monacolins K and L, or monacolin K to phytosterol is 1:4000 to 1:5.
[0027] For dosage of said compositions comprising a Monascus preparation and a phytosterol component, the amount of phytosterol should be 0.4 to 10 grams per day. For dosage of said compositions comprising a Monascus preparation and a phytosterol component, the amount of monacolins, or monacolins K and L, or monacolin K should be 1-80 mg per day.
[0028] Monascus refers to Monascus fungus (e.g., Monascus, Monascus purpureus, Monascus ruber, Monascus anka, Monascus pilosus, Monascus floridanus, Monascus pallens, Monascus sanguineus etc.) which is prepared by rice-based bio-reaction (e.g., fermentation) and which contains monacolins compounds. The Monascus preparation
- 9 -may be a raw material, or an extract, or a food item, a health product or a pharmaceutical product.
[0029] The phytosterols refer to plant sterols extracted from plants or microorganisms, and include phytosterols from grains, phytosterol from beans, rapeseed phytosterol, and vegetable oil phytosterol and their corresponding saturated type phytosterols (plant stanols, also known as phytostanols).
[0030] Given the toxic side effects of lovastatin in Monascus, one aspect of the present invention provide a new pharmaceutical composition which comprises both a Monascus component and a phytosterol component. The phytosterol component functions to inhibit the absorption of cholesterol in the intestine. This achieves the objective of further lowering the cholesterol level in the blood without increasing the dosage of the lovastatin in the Monascus component. The new pharmaceutical composition which comprises both a Monascus component and a phytosterol component has the following advantages.
[0031] The Monascus component functions to inhibit cholesterol synthesis in the human body to decrease the cholesterol level in the blood. On the other hand, the phytosterol component functions to inhibit the absorption of cholesterol in the intestine.
These two separate mechanisms can combine to achieve the goal of lowering the cholesterol level in the blood. The combination of the Monascus component and the phytosterol component together can achieve a better (e.g., 6-16% better) efficacy in terms of lowering blood cholesterol level than the use of stain alone.
[0032] According to the "Rule of 7", after using statin in reducing human serum cholesterol by about 27%, further reducing serum cholesterol by 7% requires dosage of statin to be doubled. This will greatly increase its toxicity to the liver and kidney and muscle. Phytosterols combined with statins can improve the efficacy by 6-16%
for the same therapeutic effects. By combining phytosterol with Monascus, the invention can
[0029] The phytosterols refer to plant sterols extracted from plants or microorganisms, and include phytosterols from grains, phytosterol from beans, rapeseed phytosterol, and vegetable oil phytosterol and their corresponding saturated type phytosterols (plant stanols, also known as phytostanols).
[0030] Given the toxic side effects of lovastatin in Monascus, one aspect of the present invention provide a new pharmaceutical composition which comprises both a Monascus component and a phytosterol component. The phytosterol component functions to inhibit the absorption of cholesterol in the intestine. This achieves the objective of further lowering the cholesterol level in the blood without increasing the dosage of the lovastatin in the Monascus component. The new pharmaceutical composition which comprises both a Monascus component and a phytosterol component has the following advantages.
[0031] The Monascus component functions to inhibit cholesterol synthesis in the human body to decrease the cholesterol level in the blood. On the other hand, the phytosterol component functions to inhibit the absorption of cholesterol in the intestine.
These two separate mechanisms can combine to achieve the goal of lowering the cholesterol level in the blood. The combination of the Monascus component and the phytosterol component together can achieve a better (e.g., 6-16% better) efficacy in terms of lowering blood cholesterol level than the use of stain alone.
[0032] According to the "Rule of 7", after using statin in reducing human serum cholesterol by about 27%, further reducing serum cholesterol by 7% requires dosage of statin to be doubled. This will greatly increase its toxicity to the liver and kidney and muscle. Phytosterols combined with statins can improve the efficacy by 6-16%
for the same therapeutic effects. By combining phytosterol with Monascus, the invention can
- 10 -lower the required amount of lovastatin in Monascus alone. This can be a 50%
to 66%
reduction in the dosage of lovastatin in Monascus alone. Therefore the composition comprising Monascus component and the phytosterol component is safer for human use.
[0033] Phytosterols can effectively reduce cholesterol absorption in the intestinal tract. In the gut, cholesterol from food and in bile is absorbed approximately 50%.
Inhibition of cholesterol absorption in the intestine is another important way to reduce serum cholesterol levels. It has been shown that plant sterols can effectively reduce serum cholesterol levels in patients with hyperlipidemia. The term hyperlipidemia means elevated levels of any or all lipids or lipoproteins in the blood.
Monascus combined with phytosterols may effectively eliminate the compensatory increase of cholesterol absorption caused by using Monascus lovastatin alone.
[0034] Plant sterols reduce serum cholesterol levels in patients with hyperlipidemia by reducing the absorption of cholesterol in the intestine. The mechanism of human serum cholesterol reduction is different with red yeast rice preparations. The two different mechanisms have additive efficacy effect.
[0035] Plant sterols are a class of compounds usually extracted from soybeans and other plants. Its long-term safety has gone through rigorous laboratory and clinical testing. The US Food and Drug Administration (FDA) has considered phytosterol as "Generally Recognized As Safe (GRAS)". Phytosterols combined with red yeast rice preparations can enhance lipid-lowering effect, and do not increase the toxicity to the human body.
[0036] One aspect of the invention is to increase the biological availability of the phytosterols in the intestinal tract. Experiments show that phytosterols must be dissolved in oil phase or a liquid phase to have the activity of inhibiting cholesterol absorption. The crystalline state phytosterols have inwardly hydrophilic groups, which
to 66%
reduction in the dosage of lovastatin in Monascus alone. Therefore the composition comprising Monascus component and the phytosterol component is safer for human use.
[0033] Phytosterols can effectively reduce cholesterol absorption in the intestinal tract. In the gut, cholesterol from food and in bile is absorbed approximately 50%.
Inhibition of cholesterol absorption in the intestine is another important way to reduce serum cholesterol levels. It has been shown that plant sterols can effectively reduce serum cholesterol levels in patients with hyperlipidemia. The term hyperlipidemia means elevated levels of any or all lipids or lipoproteins in the blood.
Monascus combined with phytosterols may effectively eliminate the compensatory increase of cholesterol absorption caused by using Monascus lovastatin alone.
[0034] Plant sterols reduce serum cholesterol levels in patients with hyperlipidemia by reducing the absorption of cholesterol in the intestine. The mechanism of human serum cholesterol reduction is different with red yeast rice preparations. The two different mechanisms have additive efficacy effect.
[0035] Plant sterols are a class of compounds usually extracted from soybeans and other plants. Its long-term safety has gone through rigorous laboratory and clinical testing. The US Food and Drug Administration (FDA) has considered phytosterol as "Generally Recognized As Safe (GRAS)". Phytosterols combined with red yeast rice preparations can enhance lipid-lowering effect, and do not increase the toxicity to the human body.
[0036] One aspect of the invention is to increase the biological availability of the phytosterols in the intestinal tract. Experiments show that phytosterols must be dissolved in oil phase or a liquid phase to have the activity of inhibiting cholesterol absorption. The crystalline state phytosterols have inwardly hydrophilic groups, which
- 11 -are not easily soluble in water or incorporated in emulsions, which have weak effects of inhibition of cholesterol absorption. Thus phytosterols in crystalline state have low biological availability in small intestine. In order to improve the biological availability of phytosterols in the intestine, a number of approaches can be used.
[0037] (1) Phytosterol can esterize with free or bound fatty acids in edible oil (such as vegetable oil, soybean oil, peanut oil, corn oil, sesame oil, cottonseed oil, etc.), or nutritional oils (e.g., evening primrose oil, Korean pine seed oil, linseed oil, borage oil, fish oil, cod liver oil, etc.), or perfume oils (e.g., ginger oil, naringin oil, eucalyptus oil, wintergreen oil, patchouli oil, lavender oil and the like) to form esters.
10038] (2) Phytosterol can be heated with an edible emulsifier (e.g.
stearoyl lactylate or sucrose fatty acid esters and the like), edible oils (e.g., rapeseed oil, soybean oil, peanut oil, corn oil, sesame oil , cottonseed oil, etc.), or nutritional oils (evening primrose oil, pine oil, linseed oil, borage oil, fish oil, cod liver oil) or perfume oils (e.g., ginger oil, naringin oil, eucalyptus oil, wintergreen oil, patchouli oil, lavender oil), and certain vitamins (such as vitamin E, etc.) to form a eutectic and then to cool. This interferes with the formation of phytosterol crystalline state and accelerates the emulsification of phytosterols in the gut.
[0039] (3) Phytosterol can be mixed with an edible emulsifier (e.g.
stearoyl lactylate, phosphatidylethanolamine, glyceryl monostearate or sucrose fatty acid ester, etc.), and certain vitamins, edible fatty acids (e.g. evening primrose oil, pine oil, linseed oil, borage oil, fish oil, cod liver oil, vitamin E, etc.) and dissolved in methanol, ethanol, chloroform or other organic solvents and then dried to interfere with the formation of crystalline phytosterols in the intestine and accelerate the emulsification of phytosterols [0040] (4) Phytosterol powder can be pulverized into fine particles or nanometer-range particles (e.g., 1-100 nanometer range in diameter).
[0037] (1) Phytosterol can esterize with free or bound fatty acids in edible oil (such as vegetable oil, soybean oil, peanut oil, corn oil, sesame oil, cottonseed oil, etc.), or nutritional oils (e.g., evening primrose oil, Korean pine seed oil, linseed oil, borage oil, fish oil, cod liver oil, etc.), or perfume oils (e.g., ginger oil, naringin oil, eucalyptus oil, wintergreen oil, patchouli oil, lavender oil and the like) to form esters.
10038] (2) Phytosterol can be heated with an edible emulsifier (e.g.
stearoyl lactylate or sucrose fatty acid esters and the like), edible oils (e.g., rapeseed oil, soybean oil, peanut oil, corn oil, sesame oil , cottonseed oil, etc.), or nutritional oils (evening primrose oil, pine oil, linseed oil, borage oil, fish oil, cod liver oil) or perfume oils (e.g., ginger oil, naringin oil, eucalyptus oil, wintergreen oil, patchouli oil, lavender oil), and certain vitamins (such as vitamin E, etc.) to form a eutectic and then to cool. This interferes with the formation of phytosterol crystalline state and accelerates the emulsification of phytosterols in the gut.
[0039] (3) Phytosterol can be mixed with an edible emulsifier (e.g.
stearoyl lactylate, phosphatidylethanolamine, glyceryl monostearate or sucrose fatty acid ester, etc.), and certain vitamins, edible fatty acids (e.g. evening primrose oil, pine oil, linseed oil, borage oil, fish oil, cod liver oil, vitamin E, etc.) and dissolved in methanol, ethanol, chloroform or other organic solvents and then dried to interfere with the formation of crystalline phytosterols in the intestine and accelerate the emulsification of phytosterols [0040] (4) Phytosterol powder can be pulverized into fine particles or nanometer-range particles (e.g., 1-100 nanometer range in diameter).
- 12 -[0041] These methods may be used in combination. These methods improve the phytosterol bioavailability after treatment. These can be combined with formulation consisting of Monascus. Phytosterols may also be co-formulated with red yeast (Monasccus) preparation dissolved in methanol, ethanol, chloroform, acetone or other organic solvents and then be dried. This will not only interfere with the formation of crystalline phytosterols, it can also cause phytosterols and the active ingredient in Monascus (lovastatin) to be uniformly mixed together in the formulation.
[0042] One aspect of the invention relates to mixing the phytosterol component with the Monascus component in the formulation. Mixing phytosterols component with the Monascus component involve mixing with an organic solvent, or heating and mixing, or mechanical mixing.
[0043] (1) The Monascus component and the phytosterol component are dissolved together in 70 to 100% methanol, ethanol or chloroform, an organic solvent or a mixed organic solvent, and then the mixture dried using a solvent evaporation method. In such formulations phytosterols and Monascus active ingredient (e.g., Monacolin compound) are uniformly mixed and dissolved in an organic solvent. Monascus formulation ingredients may interfere with the formation of phytosterol crystals. The Monascus component and the phytosterol component may also be dissolved in an edible oil (e.g., vegetable oil, soybean oil, peanut oil, corn oil, sesame oil, cottonseed oil, etc.), or nutritional oils (evening primrose oil, pine oil, linseed oil and phytosterols when co-solvent formulation Monascus , borage oil, fish oil, cod liver oil) or perfume oils (e.g., ginger oil, naringin oil, eucalyptus oil, wintergreen oil, patchouli oil, lavender oil) or emulsifiers (such as stearyl lactylate salt, phosphatidylethanolamine, glyceryl monostearate, sucrose fatty acid esters, or the like). Weight ratio of oil or emulsifier to phytosterol may be from 0 to 2:1.
[0044] (2) Mixing the phytosterol with red yeast formulation phytosterols may be employed in the formulation to edible oil (e.g., vegetable oil, soybean oil, peanut oil,
[0042] One aspect of the invention relates to mixing the phytosterol component with the Monascus component in the formulation. Mixing phytosterols component with the Monascus component involve mixing with an organic solvent, or heating and mixing, or mechanical mixing.
[0043] (1) The Monascus component and the phytosterol component are dissolved together in 70 to 100% methanol, ethanol or chloroform, an organic solvent or a mixed organic solvent, and then the mixture dried using a solvent evaporation method. In such formulations phytosterols and Monascus active ingredient (e.g., Monacolin compound) are uniformly mixed and dissolved in an organic solvent. Monascus formulation ingredients may interfere with the formation of phytosterol crystals. The Monascus component and the phytosterol component may also be dissolved in an edible oil (e.g., vegetable oil, soybean oil, peanut oil, corn oil, sesame oil, cottonseed oil, etc.), or nutritional oils (evening primrose oil, pine oil, linseed oil and phytosterols when co-solvent formulation Monascus , borage oil, fish oil, cod liver oil) or perfume oils (e.g., ginger oil, naringin oil, eucalyptus oil, wintergreen oil, patchouli oil, lavender oil) or emulsifiers (such as stearyl lactylate salt, phosphatidylethanolamine, glyceryl monostearate, sucrose fatty acid esters, or the like). Weight ratio of oil or emulsifier to phytosterol may be from 0 to 2:1.
[0044] (2) Mixing the phytosterol with red yeast formulation phytosterols may be employed in the formulation to edible oil (e.g., vegetable oil, soybean oil, peanut oil,
- 13 -corn oil, sesame oil, cottonseed oil, etc.), or nutritional oils (evening primrose oil, red pine oil, linseed oil, borage oil, fish oil, cod liver oil) or perfume oils (e.g., ginger oil, naringin oil, eucalyptus oil, wintergreen oil, patchouli oil, lavender oil) in free or bound the fatty acid phytosterol esters.
[0045] (3) Phytosterols and phytosterol Monascus mixed formulation may be employed in the formulation to edible oil (e.g., vegetable oil, soybean oil, peanut oil, corn oil, sesame oil, cottonseed oil, etc.), or nutritional oils (evening primrose oil, red pine oil, flaxseed oil, borage seed oil, fish oil, cod liver oil) or perfume oils (such as ginger oil, naringin oil, eucalyptus oil, wintergreen oil, patchouli oil, lavender oil, etc.) or edible emulsifier after (e.g. stearoyl lactylate, phosphatidylethanolamine, glyceryl monostearate, sucrose fatty acid ester) were dissolved in 70-100% of methanol as an organic solvent, ethanol or chloroform, then the solvent is volatilized and dried Monascus mixed with the formulation. Weight ratio of eutectic oils or emulsifier to phytosterol may be from 0 to 2:1.
[0046] (4) Monascus component or phytosterol formulations may be employed in the formulation mixed first with the edible oil (e.g., vegetable oil, soybean oil, peanut oil, corn oil, sesame oil, cottonseed oil, etc.), or nutritional oils (evening primrose oil, pine seed oil, flaxseed oil, borage seed oil, fish oil, cod liver oil) or perfume oils (such as ginger oil, naringin oil, eucalyptus oil, wintergreen oil, patchouli oil, lavender oil, etc.) or the edible emulsifier (e.g. stearoyl lactate, glyceryl monostearate, sucrose fatty acid esters, or the like) is heated eutectic mixture. Weight ratio of oil or emulsifier to phytosterol may be from 0 to 2:1.
[0047] (5) Phytosterol fine particles (may be more than 80 mesh sieve) or a mixture of phytosterols nano-particles may be cobined with Monascus powder to form a mixture formulation.
[0048] One aspect of the invention relates to the proportion of each phytosterol and
[0045] (3) Phytosterols and phytosterol Monascus mixed formulation may be employed in the formulation to edible oil (e.g., vegetable oil, soybean oil, peanut oil, corn oil, sesame oil, cottonseed oil, etc.), or nutritional oils (evening primrose oil, red pine oil, flaxseed oil, borage seed oil, fish oil, cod liver oil) or perfume oils (such as ginger oil, naringin oil, eucalyptus oil, wintergreen oil, patchouli oil, lavender oil, etc.) or edible emulsifier after (e.g. stearoyl lactylate, phosphatidylethanolamine, glyceryl monostearate, sucrose fatty acid ester) were dissolved in 70-100% of methanol as an organic solvent, ethanol or chloroform, then the solvent is volatilized and dried Monascus mixed with the formulation. Weight ratio of eutectic oils or emulsifier to phytosterol may be from 0 to 2:1.
[0046] (4) Monascus component or phytosterol formulations may be employed in the formulation mixed first with the edible oil (e.g., vegetable oil, soybean oil, peanut oil, corn oil, sesame oil, cottonseed oil, etc.), or nutritional oils (evening primrose oil, pine seed oil, flaxseed oil, borage seed oil, fish oil, cod liver oil) or perfume oils (such as ginger oil, naringin oil, eucalyptus oil, wintergreen oil, patchouli oil, lavender oil, etc.) or the edible emulsifier (e.g. stearoyl lactate, glyceryl monostearate, sucrose fatty acid esters, or the like) is heated eutectic mixture. Weight ratio of oil or emulsifier to phytosterol may be from 0 to 2:1.
[0047] (5) Phytosterol fine particles (may be more than 80 mesh sieve) or a mixture of phytosterols nano-particles may be cobined with Monascus powder to form a mixture formulation.
[0048] One aspect of the invention relates to the proportion of each phytosterol and
- 14 -Monascus component in combined preparations. Red yeast rice preparations have complex chemical composition. Currently not all of its chemical composition and biological function are elucidated. However, previous studies showed that red yeast preparations contain from about a dozen Monacolin compounds. Many of Monacolin compounds have proven to be an inhibitor of HMG-CoA which can reduce serum cholesterol and triglyceride. Monacolin K and monacolin L, especially monacolin K is often the main ingredient formulation of Monacolin based compound. In the formulations, the weight ratio of monacolins, or monacolins K and L, or monacolin K
to phytosterol is 1:4000 to 1:5.
[0049] One aspect of the invention relates to dosages of phytosterol and Monascus components when used to lower blood lipid levels. Daily dosage of the phytosterol component in the combined phytosterol and Monascus formulation is 0.4-10 g per day.
Daily dosage of the total monacolin, or the sum of monacolin K and L, or monacolin K, is 1-80 mg per day.
[0050] The synthesis, formulation of any Monascus, Monascus as a dry powder, red yeast extract, can be mixed with different forms of phytosterols, phytosterol esters such as nano phytosterol and a fatty acid, phytosterols and other substances or chemical reaction mixture consisting of mixed prescription formulation.
[0051] Example: Example 1: red yeast extract with phytosterols eutectic mixture:
the red yeast extract was dried powder with 75-100% ethanol, the extract was dried weighed after volatiles was dissolved again in suitable amount of anhydrous ethanol, goes through high efficiency liquid chromatography (HPLC) assay wherein the amount of monacolin K, and calculate monacolin K by weight thereof in the extraction.
Add phytosterols to absolute ethanol containing red yeast extract, that the weight monacolin K and phytosterol ratio being 1: 200. The red yeast extract with a mixture of phytosterols were dissolved to ethanol and dried, pulverized to a powder.
to phytosterol is 1:4000 to 1:5.
[0049] One aspect of the invention relates to dosages of phytosterol and Monascus components when used to lower blood lipid levels. Daily dosage of the phytosterol component in the combined phytosterol and Monascus formulation is 0.4-10 g per day.
Daily dosage of the total monacolin, or the sum of monacolin K and L, or monacolin K, is 1-80 mg per day.
[0050] The synthesis, formulation of any Monascus, Monascus as a dry powder, red yeast extract, can be mixed with different forms of phytosterols, phytosterol esters such as nano phytosterol and a fatty acid, phytosterols and other substances or chemical reaction mixture consisting of mixed prescription formulation.
[0051] Example: Example 1: red yeast extract with phytosterols eutectic mixture:
the red yeast extract was dried powder with 75-100% ethanol, the extract was dried weighed after volatiles was dissolved again in suitable amount of anhydrous ethanol, goes through high efficiency liquid chromatography (HPLC) assay wherein the amount of monacolin K, and calculate monacolin K by weight thereof in the extraction.
Add phytosterols to absolute ethanol containing red yeast extract, that the weight monacolin K and phytosterol ratio being 1: 200. The red yeast extract with a mixture of phytosterols were dissolved to ethanol and dried, pulverized to a powder.
- 15 -[0052] To make 1000 capsules of preparation of Monascus extract with a mixture of phytosterols (assuming in red yeast extract, monacolin K is 5% by weight).
Red yeast extract with a mixture of phytosterols as prepared above quantity: 500 g x (1 +
0.005 / red yeast extract monacolin K by weight) = 500 g x 1.1 = 550 grams.
[0053] Quantity of 800 g of diluent - red yeast extract with a mixture of phytosterols quantity = 800 g -550 g = 250 g.
[0054] Capsule size: 800 mg / capsule.
[0055] Each capsule contains 500 mg of phytosterols, Monacolin K 2.5 mg. Dosage: 1-2 tablets once, 2 times / day, 2-4 capsules / day, before or after meals.
[0056] Example 2: red yeast extract and mixing plant sterol ester Monascus dried powder was extracted with 75% ethanol, (HPLC) determination of the amount of monacolin K by efficient phase chromatography. The extract was evaporated to dryness, weighed and calculated extracts monacolin K content by weight (assuming red yeast extract monacolin K is 5% by weight).
[0057] Phytosterols measured amount of phytosterol ester (assumed phytosterols content of 50%).
[0058] To make 1000 capsules of preparation of Monascus extract with phytosterols.
[0059] 2.5 g / extraction of Monascus monacolin K was 2.5 percent by weight g grams of phytosterols /0.05=50 g.
[0060] Phytosteerol ester in an amount of: 500/50% = 1000 ml.
Red yeast extract with a mixture of phytosterols as prepared above quantity: 500 g x (1 +
0.005 / red yeast extract monacolin K by weight) = 500 g x 1.1 = 550 grams.
[0053] Quantity of 800 g of diluent - red yeast extract with a mixture of phytosterols quantity = 800 g -550 g = 250 g.
[0054] Capsule size: 800 mg / capsule.
[0055] Each capsule contains 500 mg of phytosterols, Monacolin K 2.5 mg. Dosage: 1-2 tablets once, 2 times / day, 2-4 capsules / day, before or after meals.
[0056] Example 2: red yeast extract and mixing plant sterol ester Monascus dried powder was extracted with 75% ethanol, (HPLC) determination of the amount of monacolin K by efficient phase chromatography. The extract was evaporated to dryness, weighed and calculated extracts monacolin K content by weight (assuming red yeast extract monacolin K is 5% by weight).
[0057] Phytosterols measured amount of phytosterol ester (assumed phytosterols content of 50%).
[0058] To make 1000 capsules of preparation of Monascus extract with phytosterols.
[0059] 2.5 g / extraction of Monascus monacolin K was 2.5 percent by weight g grams of phytosterols /0.05=50 g.
[0060] Phytosteerol ester in an amount of: 500/50% = 1000 ml.
- 16 -[0061] Quantity of diluent: 100 g - dried red yeast extract quantity of material =
100 g -50 g = 50 g.
[0062] 1000 ml the plant sterol ester and 50 g of red yeast extract, 50 grams diluent uniformly mixed encapsulating to make 1000 capsules.
[0063] Each capsule containing 500 mg of phytosterols, Monacolin K2.5 mg.
[0064] Dosage: 1-2 tablets or capsules once, 2 times / day, 2-4 tablets or capsules /
day, before or after meals.
[0065] Example 3: Red Yeast extract and phytosterols and edible emulsifier mixing.
[0066] Calcium stearyl lactate (or sucrose fatty acid ester or some other suitable edible emulsifier) is blended in a heat-resistant container, weight ratio being 20:1 to 1:5. Heated to about 140 degrees Celsius. At this time, both phytosterols and calcium stearoyl lactylate become a liquid. The two are mixed, cooled to room temperature to a solid, which is then broken into a powder, and through a 100 mesh sieve.
[0067] To make 1000 capsules of preparation of Monascus extract with phytosterols.
[0068] Amount of dried material: red yeast extract prepared in 1000 red yeast extract and mixing plant sterol ester capsules were prepared as follows: 2.5 g / red yeast extract monacolin K percent by weight = 2.5 g /0.05=50 g.
[0069] Phytosterols and calcium stearoyl lactylate powder mixture (weight ratio of
100 g -50 g = 50 g.
[0062] 1000 ml the plant sterol ester and 50 g of red yeast extract, 50 grams diluent uniformly mixed encapsulating to make 1000 capsules.
[0063] Each capsule containing 500 mg of phytosterols, Monacolin K2.5 mg.
[0064] Dosage: 1-2 tablets or capsules once, 2 times / day, 2-4 tablets or capsules /
day, before or after meals.
[0065] Example 3: Red Yeast extract and phytosterols and edible emulsifier mixing.
[0066] Calcium stearyl lactate (or sucrose fatty acid ester or some other suitable edible emulsifier) is blended in a heat-resistant container, weight ratio being 20:1 to 1:5. Heated to about 140 degrees Celsius. At this time, both phytosterols and calcium stearoyl lactylate become a liquid. The two are mixed, cooled to room temperature to a solid, which is then broken into a powder, and through a 100 mesh sieve.
[0067] To make 1000 capsules of preparation of Monascus extract with phytosterols.
[0068] Amount of dried material: red yeast extract prepared in 1000 red yeast extract and mixing plant sterol ester capsules were prepared as follows: 2.5 g / red yeast extract monacolin K percent by weight = 2.5 g /0.05=50 g.
[0069] Phytosterols and calcium stearoyl lactylate powder mixture (weight ratio of
- 17 -4).
[0070] 500 g + 500 g / weight ratio = 500 + 500 g / 625 g = 4.
Quantity of diluent:
175 g - dried red yeast extract quantity of material = 175 g -50 g = 125 g.
The three were uniformly mixed encapsulating 1000.
[0071] Capsule size: 800 mg / capsule each capsule containing 500 mg of phytosterols, Monacolin K 2.5 mg Dosage: 1-2 tablets once, 2 times / day, 2-4 capsules / day, before or after meals.
[0072] Example 4: red yeast extract phytosterols and / or nutritional edible oil or perfume oil mixed with fish oil phytosterols (or evening primrose oil, pine oil, linseed oil, borage oil and household cooking oil etc.) blended in a heat-resistant container. 20:1 weight ratio to 5. Heated to about 140 degrees Celsius. At this time, both phytosterols and calcium stearoyl lactylate into a liquid. The two mixed, cooled to room temperature pulverization.
[0073] Amount of dried material red yeast extract prepared in 1000 red yeast extract and mixing plant sterol ester capsules were prepared as follows: 2.5 g / red yeast extract monacolin K = 2.5 percent by weight g grams /0.05=50 phytosterols and fish oil prepared above (weight ratio of 4): 500 g + 500 g / weight ratio = 500 + 500 g g / 625 g =4.
[0074] Quantity of diluent: 175 g - dried red yeast extract quantity of material =
175 g -50 g = 125 g.
[0075] The three were uniformly mixed encapsulating 1000 capsules.
[0076] Capsule size: 800 mg / capsule each capsule containing 400 mg of
[0070] 500 g + 500 g / weight ratio = 500 + 500 g / 625 g = 4.
Quantity of diluent:
175 g - dried red yeast extract quantity of material = 175 g -50 g = 125 g.
The three were uniformly mixed encapsulating 1000.
[0071] Capsule size: 800 mg / capsule each capsule containing 500 mg of phytosterols, Monacolin K 2.5 mg Dosage: 1-2 tablets once, 2 times / day, 2-4 capsules / day, before or after meals.
[0072] Example 4: red yeast extract phytosterols and / or nutritional edible oil or perfume oil mixed with fish oil phytosterols (or evening primrose oil, pine oil, linseed oil, borage oil and household cooking oil etc.) blended in a heat-resistant container. 20:1 weight ratio to 5. Heated to about 140 degrees Celsius. At this time, both phytosterols and calcium stearoyl lactylate into a liquid. The two mixed, cooled to room temperature pulverization.
[0073] Amount of dried material red yeast extract prepared in 1000 red yeast extract and mixing plant sterol ester capsules were prepared as follows: 2.5 g / red yeast extract monacolin K = 2.5 percent by weight g grams /0.05=50 phytosterols and fish oil prepared above (weight ratio of 4): 500 g + 500 g / weight ratio = 500 + 500 g g / 625 g =4.
[0074] Quantity of diluent: 175 g - dried red yeast extract quantity of material =
175 g -50 g = 125 g.
[0075] The three were uniformly mixed encapsulating 1000 capsules.
[0076] Capsule size: 800 mg / capsule each capsule containing 400 mg of
- 18 -phytosterols, Monacolin K 2.5 mg Dosage: 1-2 tablets once, 2 times / day, 2-4 capsules / day, before or after meals clothes.
[0077] Example 5: Monascus phytosterols and / emulsifier mixture directly mixing the edible red yeast to break it into a powder mill, measured monacolin K
content by weight (e.g., 1%).
[0078] 1000 Monascus and Monascus phytosterols mixing amount of powder capsule prepared as follows: Percentage of 2.5 grams / monacolin K /0.01=250 g weight = 2.5 g.
[0079] Prepared in Example 3 phytosterols and calcium stearoyl lactylate powder mixture (weight ratio of 4) in an amount of: 500 g + 500 g / weight ratio =
500 + 500 g g / 625 g = 4. Quantity of diluent: 275 g - red yeast powder content = 175 g -250 g = 25 g. The three were uniformly mixed encapsulating 1000 capsules.
[0080] Capsule size: 900 mg / capsule each capsule containing 500 mg of phytosterols, Monacolin K 2.5 mg. Dosage: 1-2 tablets or capsules once, 2 times / day, 2-4 capsules / day, before or after meals.
[0081] As will be apparent to those skilled in the art in the light of the foregoing disclosure, many alterations and modifications are possible in the practice of this invention. The scope of the claims should not be limited by the preferred embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.
[0082] References: Joven J, Vilella E, Camps J, Masana L, Turner PR, Simo JM, Villabona C. Toxicity of lovastatin in rats with experimentally induced nephrotic syndrome.Nephron.1990; 56 (4): 3992.
[0077] Example 5: Monascus phytosterols and / emulsifier mixture directly mixing the edible red yeast to break it into a powder mill, measured monacolin K
content by weight (e.g., 1%).
[0078] 1000 Monascus and Monascus phytosterols mixing amount of powder capsule prepared as follows: Percentage of 2.5 grams / monacolin K /0.01=250 g weight = 2.5 g.
[0079] Prepared in Example 3 phytosterols and calcium stearoyl lactylate powder mixture (weight ratio of 4) in an amount of: 500 g + 500 g / weight ratio =
500 + 500 g g / 625 g = 4. Quantity of diluent: 275 g - red yeast powder content = 175 g -250 g = 25 g. The three were uniformly mixed encapsulating 1000 capsules.
[0080] Capsule size: 900 mg / capsule each capsule containing 500 mg of phytosterols, Monacolin K 2.5 mg. Dosage: 1-2 tablets or capsules once, 2 times / day, 2-4 capsules / day, before or after meals.
[0081] As will be apparent to those skilled in the art in the light of the foregoing disclosure, many alterations and modifications are possible in the practice of this invention. The scope of the claims should not be limited by the preferred embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.
[0082] References: Joven J, Vilella E, Camps J, Masana L, Turner PR, Simo JM, Villabona C. Toxicity of lovastatin in rats with experimentally induced nephrotic syndrome.Nephron.1990; 56 (4): 3992.
- 19 -[0083] Fernandez Zatarain G, Navarro V, Garcia H, Villatoro J, Calvo C.
Rhabdomyolysis and acute renal failure associated with lovastatin.Nephron.1994; 66 (4): 4833.
[0084] Jiyuan Ma, Yongguo Li, Qing Ye, Jing Li, Yanjun Hua, Dajun Ju, Decheng Zhang, Raymond Cooper, and MichaelChang.Constituents of Red Yeast Rice, a Traditional Chinese Food and Medicine. J. Agric. Food Chem.2000; 48 (11):
52204.
[0085] Ricky YK Man, Edward G. Lynn, Filly Cheung, PatriciaS.Y.Tsang and Karmin 0. Cholestin inhibits cholesterol synthesis and secretion in hepatic cells (HepG2). Molecular and Cellular Biochemistry 2002; 233 (1-2): 153 [0086] Prasad GV, Wong T, Meliton G, Bhaloo S. Rhabdomyolysis due to red yeast rice (Monascus purpureus) in a renal transplant recipient.Transplantation.2002 27; 74 (8): 12006.
[0087] Heber D, Lembertas A, Lu QY, Bowerman S, Go VL.Ananalysis of nine proprietary Chinese red yeast rice dietary supplements: implications of variability in chemical profile and contents. J Altern Complement Med 2001; 7 (2): 1337.
[0088] Simons LA. Additive effect of plant sterol-ester margarine and cerivastatin in lowering low ¨density lipoprotein cholesterol primary hypercholesterolemia.
Am J
Cardio1.2002 in; 90 (7): 7378.
[0089] Gylling H, Miettinen TA.Effects of inhibiting cholesterol absorption and synthesis on cholesterol and lipoprotein metabolism in hypercholesterole micnon-insulin-dependent diabetic men.J Lipid Res.1996; 37 (8): 1776-85.
[0090] Gylling H, Radhakrishnan R, Miettinen TA. Reduction of serum cholesterol
Rhabdomyolysis and acute renal failure associated with lovastatin.Nephron.1994; 66 (4): 4833.
[0084] Jiyuan Ma, Yongguo Li, Qing Ye, Jing Li, Yanjun Hua, Dajun Ju, Decheng Zhang, Raymond Cooper, and MichaelChang.Constituents of Red Yeast Rice, a Traditional Chinese Food and Medicine. J. Agric. Food Chem.2000; 48 (11):
52204.
[0085] Ricky YK Man, Edward G. Lynn, Filly Cheung, PatriciaS.Y.Tsang and Karmin 0. Cholestin inhibits cholesterol synthesis and secretion in hepatic cells (HepG2). Molecular and Cellular Biochemistry 2002; 233 (1-2): 153 [0086] Prasad GV, Wong T, Meliton G, Bhaloo S. Rhabdomyolysis due to red yeast rice (Monascus purpureus) in a renal transplant recipient.Transplantation.2002 27; 74 (8): 12006.
[0087] Heber D, Lembertas A, Lu QY, Bowerman S, Go VL.Ananalysis of nine proprietary Chinese red yeast rice dietary supplements: implications of variability in chemical profile and contents. J Altern Complement Med 2001; 7 (2): 1337.
[0088] Simons LA. Additive effect of plant sterol-ester margarine and cerivastatin in lowering low ¨density lipoprotein cholesterol primary hypercholesterolemia.
Am J
Cardio1.2002 in; 90 (7): 7378.
[0089] Gylling H, Miettinen TA.Effects of inhibiting cholesterol absorption and synthesis on cholesterol and lipoprotein metabolism in hypercholesterole micnon-insulin-dependent diabetic men.J Lipid Res.1996; 37 (8): 1776-85.
[0090] Gylling H, Radhakrishnan R, Miettinen TA. Reduction of serum cholesterol
- 20 -in postmenopausal women with previous myocardial infarction and cholesterol malabsorption induced by dietary sitostanol ester margarine: women and dietary sitostanol. Circulation.1997; 96 (12): 4226-31 [0091] Roberts WC. The rule of 5 and the rule of 7 in lipid-lowering by statin drugs.
Am J Cardio1.1997; 80 (1): 106 [0092] Gremaud G, Dalan E, Piguet C, Baumgartner M, Ballabeni P, Decarli B, Leser ME, Berger A, Fay LB. Effects of non-esterified stanols in a liquid emulsion on cholesterol absorption and synthesis in hypercholesterolemic men. Eur J
Nutr.2002; 41 (2): 54-60.
[0093] Matvienko OA, Lewis DS, Swanson M, Arndt B, Rainwater DL, Stewart J, Alekel DL. A single daily dose of soy bean phytosterols in ground beef decreases serum total cholesterol and LDL cholesterol in young, mildly hypercholesterolemic men. Am J Clin Nutr 2002; 76 (1): 5711.
[0094] Mussner MJ, Parhofer KG, Von Bergmann K, Schwandt P, Broedl U, Otto C. Effects of phytosterol ester-enriched margarine on plasma lipoproteins in mild to moderate hypercholesterolemia are related to basal cholesterol and fat intake.
Metabolism 2002, 51(2): 18912.
[0095] Endo A. Monacolin K, a new hypocholesterolemic agent produced by a Monascus species. J Antibiot (Tokyo) .1979; 32 (8): 85213.
[0096] Endo A, Hasumi K, Negishi S.Monacolins J and L, new inhibitors of cholesterol biosynthesis produced by Monascus ruber. J Antibiot (Tokyo) .1985;
38 (3):
Am J Cardio1.1997; 80 (1): 106 [0092] Gremaud G, Dalan E, Piguet C, Baumgartner M, Ballabeni P, Decarli B, Leser ME, Berger A, Fay LB. Effects of non-esterified stanols in a liquid emulsion on cholesterol absorption and synthesis in hypercholesterolemic men. Eur J
Nutr.2002; 41 (2): 54-60.
[0093] Matvienko OA, Lewis DS, Swanson M, Arndt B, Rainwater DL, Stewart J, Alekel DL. A single daily dose of soy bean phytosterols in ground beef decreases serum total cholesterol and LDL cholesterol in young, mildly hypercholesterolemic men. Am J Clin Nutr 2002; 76 (1): 5711.
[0094] Mussner MJ, Parhofer KG, Von Bergmann K, Schwandt P, Broedl U, Otto C. Effects of phytosterol ester-enriched margarine on plasma lipoproteins in mild to moderate hypercholesterolemia are related to basal cholesterol and fat intake.
Metabolism 2002, 51(2): 18912.
[0095] Endo A. Monacolin K, a new hypocholesterolemic agent produced by a Monascus species. J Antibiot (Tokyo) .1979; 32 (8): 85213.
[0096] Endo A, Hasumi K, Negishi S.Monacolins J and L, new inhibitors of cholesterol biosynthesis produced by Monascus ruber. J Antibiot (Tokyo) .1985;
38 (3):
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Claims (43)
1. A composition for reducing blood lipid level, wherein the composition comprises a Monascus component and a phytosterol component.
2. The composition according to claim 1, wherein the phytosterol component comprises a phytosterol or a phytosterol ester.
3. The composition according to claim 1, wherein the phytosterol component comprises a chemical derivative of a phytosterol.
4. The composition according to claim 1, wherein the Monascus component is derived from one or more of Monascus fungi.
5. The composition according to claim 4, wherein the one or more of Monascus fungi comprises one or more of Monascus purpureus, Monascus ruber,Monascus anka, Monascus pilosus, Monascus floridanus, Monascus pallens, and Monascus sangutneus.
6. The composition according to any one of claims 1 to 5, wherein the Monascus component comprises Monascus powder, or Monascus extract, or Monascus extract powder, or Monascus solution, or a combination thereof.
7. The composition according to any one of claims 1 to 6, wherein the phytosterol component comprises phytosterol fine particles.
8. The composition according to claim 7, wherein the phytosterol fine particles comprises fine particles of mesh size number 80 or above 80.
9. The composition according to claim 7, wherein the phytosterol fine particles are in the nanometer range, between 1 to 100 nm in size.
10. The composition according to claim 9, wherein the phytosterol fine particles are generated by mixing phytosterol with an edible emulsifier and going through an emulsification process.
11. The composition according to claim 10, wherein the edible emulsifier comprises sucrose fatty acid ester.
12. The composition according to claim 7, wherein the phytosterol component comprises an ester of phytosterol with either free or bound fatty acids.
13. The composition according to any one of claims 1 to 12, wherein the composition is provided as a capsule, or a tablet, or a chewing gum, or a gummy, or a liquid solution for drinking.
14. The composition according to any one of claims 1 to 12, wherein the composition is provided in a beverage, or a food item, or a pharmaceutical item.
15. The composition according to any one of claims 1 to 14, wherein the phytosterol component comprises a phytosterol which is first mixed with an edible oil, or a nutritional oil, or a spice oil to form an ester with a fatty acid in said edible oil, or nutritional oil, or spice oil.
16. The composition according to claim 15, wherein the weight ratio of said edible oil or nutritional oil or spice oil to phytosterol is 0 to 2:1.
17. The composition according to claim 16, wherein the weight ratio of said edible oil or nutritional oil or spice oil to phytosterol is 1:5 to 2:1.
18. The composition according to any one of claims 1 to 17, wherein the weight ratio of monacolins in the Monascus component to phytosterol in the phytosterol component is 1:4000 to 1:5.
19. The composition according to any one of claims 1 to 17, wherein the weight ratio of monacolins K and L in the Monascus component to phytosterol in the phytosterol component is 1:4000 to 1:5.
20. The composition according to any one of claims 1 to 17, wherein the weight ratio of monacolin K in the Monascus component to phytosterol in the phytosterol component is 1:4000 to 1:5.
21. The composition according to any one of claims 1 to 17, wherein the weight ratio of monacolin K in the Monascus component to phytosterol in the phytosterol component is 1:4000 to 1:200.
22. The composition according to any one of claims 1 to 17, wherein the weight ratio of monacolin K in the Monascus component to phytosterol in the phytosterol component is 1:200 to 1:5.
23. The composition according to claim 15, wherein the edible oil comprises one or more of vegetable oil, soybean oil, peanut oil, corn oil, sesame oil, cottonseed oil.
24. The composition according to claim 15, wherein the nutritional oil comprises one or more of evening primrose oil, pine oil, linseed oil, borage seed oil, fish oil, cod liver oil.
25. The composition according to claim 15, wherein the spice oil comprises one or more of ginger oil, naringin oil, eucalyptus oil, wintergreen oil, patchouli oil, lavender oil.
26. A method of manufacturing a composition for reducing blood lipid level, wherein the composition comprises a Monascus component and a phytosterol component, the method comprises the step of co-dissolving the Monascus component and the phytosterol component in an organic solvent and then drying the solvent.
27. The method according to claim 26, wherein the organic solvent is methanol, ethanol or chloroform.
28. A method of manufacturing a composition for reducing blood lipid level, wherein the composition comprises a Monascus component and a phytosterol component, the method comprising the step of co-dissolving the Monascus component and the phytosterol component in an edible oil, or a nutritional oil, or a spice oil, or an edible emulsifier.
29. A method of manufacturing a composition for reducing blood lipid level, wherein the composition comprises a Monascus component and a phytosterol component, the method comprising the steps of dissolving the Monascus component or the phytosterol component in an edible oil, or a nutritional oil, or a spice oil, or an edible emulsifier, and then dissolving said resultant solution in an organic solvent, and then drying the solvent.
30. The method according to claim 29, wherein the organic solvent is methanol, ethanol or chloroform.
31. The composition according to claim 18, wherein the composition is provided as a capsule or a tablet, wherein each capsule or tablet contains monacolins in a daily dosage amount of 1-80 mg, and each capsule or tablet contains phytosterol in a daily dosage amount of 0.4-10 g.
32. The composition according to claim 31, wherein the phytosterol component in the composition can reduce the absorption of cholesterol in the gut, and the monacolins in the Monascus component can reduce the biosynthesis of cholesterol in the liver.
33. The composition according to claim 32, wherein the composition can achieve a desired lipid-lowering effect with less than 50% of the amount of monacolins, as compared to conventional medications that contain monacolin compounds alone.
34. The composition according to claim 32, wherein the composition can achieve a desired lipid-lowering effect with reduced toxic side effects on the kidney, liver, and muscles, as compared to conventional medications that contain monacolin compounds alone.
35. The composition according to claim 32, wherein the composition can lower blood lipid levels more effectively than conventional medications that contain monacolin compounds alone.
36. The composition according to claim 32, wherein the composition can lower blood lipid levels more effectively by an extent of 6% to 16% than conventional medications that contain monacolin compounds alone.
37. The composition according to claim 18, wherein the phytosterol component comprises only phytosterol compounds that have at least two carbon-carbon double bonds.
38. The composition according to claim 18, wherein the phytosterol component comprises only phytosterol compounds that have at least three carbon-carbon double bonds.
39. The composition according to claim 18, wherein the phytosterol component comprises only phytostanol compounds that have zero carbon-carbon double bonds.
40. The composition according to claim 18, wherein the phytosterol component comprises only plant-derived or synthetic phytostanol compounds that have zero carbon-carbon double bonds.
41. The composition according to claim 18, wherein the phytosterol component comprises phytosterol compounds derived from legume species.
42. The composition according to claim 18, wherein the phytosterol component comprises phytostanol compounds derived from grain species.
43. The composition according to claim 18, wherein the Monascus component is free of citrinin.
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2018
- 2018-10-01 CA CA3019312A patent/CA3019312A1/en not_active Abandoned
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109699887A (en) * | 2019-01-24 | 2019-05-03 | 山西潞安石圪节智华生物科技有限公司 | A kind of peony seed oil blood fat reducing soft capsule and preparation method thereof |
| CN109699887B (en) * | 2019-01-24 | 2022-02-22 | 山西潞安矿业(集团)有限责任公司 | Peony seed oil soft capsule for reducing blood fat and preparation method thereof |
| CN111513155A (en) * | 2020-05-21 | 2020-08-11 | 云南中医药大学 | Composition for preventing and treating lipid metabolism disorder |
| CN111513155B (en) * | 2020-05-21 | 2022-11-08 | 云南中医药大学 | Composition for preventing and treating lipid metabolism disorder |
| CN111803597A (en) * | 2020-08-20 | 2020-10-23 | 西藏月王药诊生态藏药科技有限公司 | Highland barley monascus granules and preparation method thereof |
| CN113455552A (en) * | 2021-07-22 | 2021-10-01 | 上海太太乐食品有限公司 | Healthy strong-fragrance edible oil and preparation method thereof |
| CN116035210A (en) * | 2022-12-30 | 2023-05-02 | 广州白云山汉方现代药业有限公司 | Method for solving layering of content and application of method in preparation of plant sterol ester red yeast soft capsules |
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